The present invention relates to propylene glycol hyaluronate esters and agent for external use to skin, which refers to xe2x80x9cskin preparations for external usexe2x80x9d hereinafter, containing said propylene glycol hyaluronate esters. Skin preparations for external use according to the present invention can be widely used as cosmetic and pharmaceutical products because of their excellent viscosity stability, emulsifiability, hydration power and moisturizing effect.
Dry skin is caused by excessive loss of moisture from the surface of the skin exposed to dry air or cleansing. In these days, various environmental chemical substances also inhibit skin functions such as lipid secretion to often invite dry skin. Therefore, there is a demand for a skin preparation for external use to prevent dry skin and provide an excellent moisturizing effect.
Various active compounds having a moisturizing effect have been provided, which are mainly based on water-soluble polyols. Some of them including propylene glycols have already been commercialized. However, many of commercialized moisturizing compounds are associated with uncomfortable feel during application or insufficient moisturizing effect, so that there is still a demand for the development of a new moisturizing compound.
An alternative moisturizing compound is sodium hyaluronate, which draws special interest as a valuable compound because of high hydration effect. However, aqueous solutions of sodium hyaluronate have a disadvantage in stability, which is high at neutral pH range but lowered in acidic solutions or salt solutions. This leads to the problem that the moisturizing effect cannot be effectively produced under some storage conditions or application conditions during use as cosmetics or the like, and there is a need for a solution thereto.
In view of these problems of the prior art, our studies were devoted to provide a material that stably exists even in low-pH solutions or salt solutions and has excellent emulsifiability and hydration effect. Thus, an object of the present invention is to provide a compound that can be widely used as cosmetic and pharmaceutical products because of excellent viscosity stability, emulsifiability, hydration power and moisturizing effect.
As a result of careful studies to attain the above object, we accomplished the present invention on the basis of the finding that propylene glycol hyaluronate esters satisfying specific conditions have excellent properties.
Accordingly, the present invention provides propylene glycol hyaluronate esters having an esterification degree of 10-90%, preferably 20-80%, more preferably 30-70%, even more preferably 40-60%. The present invention also provides propylene glycol hyaluronate esters having a limiting viscosity of 3-35 dL/g, preferably 11-27 dL/g, more preferably 14-20 dL/g. Especially preferred propylene glycol hyaluronate esters of the present invention are compounds having an esterification degree of 40-60% and a limiting viscosity of 14-20 dL/g.
Propylene glycol hyaluronate esters of the present invention are preferably combined with imidazoline-based amphoteric surfactants such as 2-lauryl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine and 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine.
The present invention also provides skin preparations for external use containing said propylene glycol hyaluronate esters. Skin preparations for external use according to the present invention are useful as moisturizers and emulsifiers, especially as emulsifiers for low-pH systems, emulsifiers for cation-containing systems and high-hydration emulsifiers.
Numerical ranges used herein include both limits.
Propylene glycol hyaluronate esters and skin preparations for external use according to the present invention will now be explained in detail.
Propylene glycol hyaluronate esters of the present invention are compounds having an esterification degree of 10-90% or a limiting viscosity of 3-35 dL/g. The esterification degree is preferably 20-80%, more preferably 30-70%, even more preferably 40-60%. The limiting viscosity is preferably 11-27 dL/g, more preferably 13-23 dL/g, even more preferably 14-20 dL/g.
Propylene glycol hyaluronate esters of the present invention are preferably compounds having an esterification degree of 10-90% and a limiting viscosity of 3-35 dL/g, more preferably compounds having an esterification degree of 20-80% and a limiting viscosity of 11-27 dL/g, even more preferably compounds having an esterification degree of 30-70% and a limiting viscosity of 13-23 dL/g, most preferably compounds having an esterification degree of 40-60% and a limiting viscosity of 14-20 dL/g.
As used herein, the xe2x80x9cesterification degreexe2x80x9d means the proportion of esterified carboxylates among those forming hyaluronic acid. The limiting viscosity of propylene glycol hyaluronate esters can be determined according to the method of Laurent et al. (T. C. Laurent et al. Biochem. Biophys. Acta, 42(1960)476-485).
The type and structure of the hyaluronic acid moiety forming propylene glycol hyaluronate esters of the present invention are not specifically limited. The molecular weight of hyaluronic acid, which is a polysaccharide having repeating units of a disaccharide consisting of D-glucuronic acid and N-acetyl-D-glucosamine, is not specifically limited so far as the limiting viscosity of the resulting propylene glycol esters falls within said range. Hyaluronic acid used herein may be synthesized or purified from natural origins by known means. Substituents on D-glucuronic acid and N-acetyl-D-glucosamine forming ihyaluronic acid may be partially derivatized unless the effects of the present invention are excessively hindered. For example, hydroxyl groups may be substituted by alkoxy or other groups. These substitutions can be appropriately carried out within the scope of those skilled in the art.
In propylene glycol hyaluronate esters of the present invention, acid moieties and ester moieties may be localized in their molecules or may be widely distributed. However, those having two or more molecules of hyaluronic acid crosslinked via propylene glycol are excluded.
Processes for preparing propylene glycol hyaluronate esters of the present invention are not specifically limited. An especially preferred process involves reacting a mixture of hyaluronic acid and sodium hyaluronate with propylene oxide. More specifically, sodium hyaluronate is first partially converted into hyaluronic acid in the presence of a hydrochloric acid/ethanol solution or the like and then the reaction mixture is washed with ethanol to give a mixture of hyaluronic acid and sodium hyaluronate. Then, this mixture is esterified with a solution of propylene oxide in ethanol. Preferably, the temperature of the esterification reaction here is 50-80xc2x0 C. and the reaction time is about 1-10 hours. After reaction, the reaction product may be washed with ethanol, neutralized with a solution of sodium acetate in ethanol, washed with ethanol again, and then dried. According to this process, a propylene glycol hyaluronate ester having the intended effects of the present invention can be efficiently prepared.
Propylene glycol hyaluronate esters of the present invention are quite useful as ingredients of skin preparations for external use. Propylene glycol hyaluronate esters of the present invention are compounds showing excellent viscosity stability in low-pH systems and cation-containing systems and also showing high emulsifiability, hydration power and moisturizing effect. Thus, skin preparations for external use containing a propylene glycol hyaluronate ester of the present invention are useful as moisturizers, emulsifiers for low-pH systems, emulsifiers for cation-containing systems and high-hydration emulsifiers.
Skin preparations for external use according to the present invention were found to have especially high stability and excellent moisturizing effect so that they provide appropriate moisture to the surface of the skin to keep smoothness. That is, skin preparations for external use according to the present invention can keep moisture in the skin for a long period. Such an effect of the present invention is especially remarkable in propylene glycol hyaluronate esters satisfying the conditions described above. It could not be expected that such compounds are much effective than similar hyaluronate esters departing from the conditions described above.
For example, skin preparations for external use according to the present invention can be used as cosmetic or pharmaceutical products, such as toilet soaps, shampoos, face washes, rinses, eye creams, eye shadows, creams and/or emulsions, lotions, perfumes, face powders, cosmetic oils, cosmetic products for hair and scalp, hair dyes, solid perfumes, powders, packs, shaving creams, shaving lotions, suntan oils, sunscreen oils, suntan lotions, sunscreen lotions, suntan creams, sunscreen creams, foundations, powder perfumes, cheek colors, mascaras, eyebrow colors, nail creams, nail enamels, nail enamel removers, hair washes, bath cosmetics, lip colors, lip creams, eyeliners, dentrifrices, deodorant products, eaux de cologne, hair growers, etc. Skin preparations for external use according to the present invention may also be used as ointments or fomentations.
Skin preparations for external use according to the present invention may also contain various ingredients other than said propylene glycol hyaluronate esters depending on the purpose of use such as improvement of emollient effect, improvement of feel of use, moderation of dehydration after use, improvement of solubility, improvement of emulsifiability, improvement of emulsification stability, improvement of compatibility with oily ingredients, moderation of feel of stretch after use, improvement of skin fit, improvement of spreadability on the skin, moderation of greasiness, prevention of dry skin, enhancement of skin-improving effect, improvement of skin-protecting effect, keratin improvement, normalization of epidermal keratinization (prevention of parakeratosis, prevention of acanthosis and inhibition of disorder of epidermal lipid metabolism via promoted turnover of the skin), moderation of xeroderma such as senile xeroderma, improvement of dry skin conditions such as crack or desquamation, inhibition of the formation of wrinkles, removal of wrinkles, wound healing, prevention and improvement of pigmentation, antiaging, moderation of dandruff or itch, moderation of loss of hair, prevention and treatment of scalp diseases, improvement of setting, improvement of softness, improvement of elasticity, glossing, suppression of melanogenesis, prevention of sunburn, etc.
Depending on the purpose of use, skin preparations for external use according to the present invention may appropriately contain other ingredients such as fats and oils, phospholipids, UV absorbers, IR absorbers, emulsifiers, surfactants, preservatives, antifungal agents, antioxidants, whitening agents, vitamins, amino acids, hormones, peptides, bioactive plant extracts, fluorescent materials, pigments, dyes, perfumes, scrubbing agents, sequestrants, binders, fillers, thickeners, sugars, nutrient ingredients, pH modulators, chelating agents, antibacterials, keratin improvers, keratolytic agents, antibiotics, skin penetration enhancers, blood circulation promoters, antiphlogistics, cytotonic agents, antiinflammatory agents, analgesics, skin softeners, emollients, woundhealing agents, metabolism enhancers, etc. Additional moisturizing ingredients other than propylene glycol hyaluronate esters of the present invention may also be contained.
Suitable fats and oils for use in skin preparations for external use according to the present invention include fatty acids such as oleic acid, behenic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, linolic acid, xcex3-linolenic acid, columbic acid, eicosa-(n-6,9,13)-trienoic acid, arachidonic acid, xcex1-linolenic acid, tymnodonic acid, hexaenoic acid; ester oils such as pentaerythritol-tetra-2-ethyl hexanoate, isopropyl myristate, butyl stearate, hexyl laurate, octyldodecyl myristate, diisopropyl adipate, diisopropyl sebacate; waxes such as beeswax, spermaceti, lanolin, carnauba wax, candelilla wax, vaseline; animal and plant oils such as mink oil, olive oil, castor oil, cacao butter, palm oil, cod liver oil, beef tallow, butter fat, evening primrose oil, rice bran oil, squalane; mineral oils such as hydrocarbon oils, liquid paraffin; silicone oils such as methyl phenyl silicone, dimethyl silicone; higher alcohols such as lauryl alcohol, stearyl alcohol, oleyl alcohol, cetyl alcohol, 2-octyl dodecanol, 2-decyl tetradecanol and derivatives thereof. Suitable organic acids include xcex1-hydroxy acid, hydroxycarboxylic acid, dicarboxylic acid, glycyrrhizic acid, glycyrrhetic acid, mevalonic acid (mevalolactone).
Suitable phospholipids for use in skin preparations for external use according to the present invention include monoacylester-type glycerophospholipids and diacylester-type glycerophospholipids. Specific examples include lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylserine, lysophosphatidylinositol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phosphatidylglycerol, phosphatidic acid, sphingomyelin. Naturally derived lecithins such as yolk and hydrogenates of the compounds mentioned above may also be used.
Suitable UV absorbers for use in skin preparations for external use according to the present invention include oxybenzone (2-hydroxy-4-methoxybenzophenone), oxybenzonesulfonic acid, oxybenzonesulfonic acid (trihydrate), guaiazulene, ethylene glycol salicylate, octyl salicylate, dipropylene glycol salicylate, phenyl salicylate, homomenthyl salicylate, methyl salicylate, methyl diisopropylcinnamate, cinoxate (2-ethoxyethyl p-methoxycinnamate), glyceryl mono-2-ethylhexyl-di-p-methoxycinnamate, 2,2xe2x80x2-dihydroxy-4-methoxybenzophenone, sodium 2,2xe2x80x2-dihydroxy-4-methoxybenzophenone-5,5xe2x80x2-disulfonate, 2,4-dihydroxybenzophenone, 2,3,4,4xe2x80x2-tetrahydroxybenzophenone, p-aminobenzoic acid, ethyl p-aminobenzoate, glyceryl p-aminobenzoate, amyl p-dimethylaminobenzoate, 2-ethylhexyl p-dimethylaminobenzoate, p-hydroxyanisol, 2-ethylhexyl p-methoxycinnamate, isopropyl p-methoxycinnamate, diisopropyl cinnamate ester, 2-(2-hydroxy-5-methylphenyl)benzotriazole, sodium 2-hydroxy-4-methoxybenzophenone-5-sulfonate, 4-tert-butyl-4xe2x80x2-methoxybenzoylmethane, 2-ethylhexyl salicylate, glyceryl p-monobenzoate, methyl orthoaminobenzoate, 2-hydroxy-4-methoxybenzophenone, amyl p-dimethylaminobenzoate, 2-phenylbenzimidazol-5-sulfonic acid, 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid, dicaproyl trioleate, 2-ethoxyethyl p-methoxycinnamate, butylmethoxy-dibenzoylmethane, glyceryl mono-2-ethylhexanoyl-di-p-methoxybenzophenone, 2-ethylhexyl-2-cyano-3,3xe2x80x2-diphenylacrylate, 2,2xe2x80x2-dihydroxy-4-methoxybenzophenone, ethyl 4-bishydroxypropyl aminobenzoate.
Suitable emulsifiers and surfactants for use in skin preparations for external use according to the present include nonionic surfactants, anionic surfactants, cationic surfactants and amphoteric surfactants.
Examples of nonionic surfactants include sorbitan esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan monoisostearate; polyoxyethylene sorbitan esters such as polyoxyethylene sorbitan monoisostearate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate; glycerol ethers such as glycerol monoisostearate, glycerol monomyristate; polyoxyethylene glycerol ethers such as polyoxyethylene glycerol monoisostearate, polyoxyethylene glycerol monomyristate; polyglycerin fatty acid esters such as diglyceryl monostearate, decaglyceryl decaisostearate, diglyceryl diisostearate; glycerin fatty acid esters such as glyceryl monocaprate, glyceryl monolaurate, glycerylmonomyristate, glycerylmonopalminate, glycerylmonooleate, glyceryl monostearate, glyceryl monolinoleate, glyceryl monoisostearate, glyceryl monodilinoleate, glyceryl monodicaprate; polyoxyethylene glycerin fatty acid esters such as polyoxyethylene glyceryl monomyristate, polyoxyethylene glyceryl monooleate, polyoxyethylene glyceryl monostearate; polyoxyethylene branched alkyl ethers such as polyoxyethylene octyldodecyl alcohol, polyoxyethylene-2-decyltetradecyl alcohol; polyoxyethylene alkyl ethers such as polyoxyethylene oleyl alcohol ether, polyoxyethylene cetyl alcohol ether; polyoxyethylene hydrogenated castor oil fatty acid esters such as polyoxyethylene hydrogenated castor oil, polyoxyethylene dihydrocholesterol ether, polyoxyethylene hydrogenated castor oil isostearate; polyoxyethylene alkyl aryl ethers such as polyoxyethylene octyl phenol ether.
Examples of anionic surfactants include salts of higher fatty acids such as oleic acid, stearic acid, isostearic acid, palmitic acid, myristic acid, behenic acid, for example, diethanolamine salts, triethanolamine salts, amino acid salts, potassium salts, sodium salts, ether carboxylic acid alkali salts, N-acylamino acid salts, N-acyl sarcosinates, higher alkyl sulfonates. Examples of cationic or amphoteric surfactants include alkyl quaternary ammonium salts, polyamines and alkyl amine salts.
Skin preparations for external use according to the present invention are preferably used in combination with amphoteric surfactants, among which imidazoline-based amphoteric surfactants are especially preferred. As used herein, the xe2x80x9cimidazoline-based amphoteric surfactantsxe2x80x9d refer to amphoteric surfactants containing an imidazoline ring in their molecules and amphoteric surfactants having an opened imidazoline ring. Examples of imidazoline-based amphoteric surfactants include 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine, sodium N-cocoyl-Nxe2x80x2-carboxylethyl-Nxe2x80x2-hydroxyethyl ethylenediamine, disodium N-cocoyl-Nxe2x80x2-carboxymethoxyethyl-Nxe2x80x2-carboxymethyl ethylenediamine and disodium N-cocoyl-Nxe2x80x2-carboxymethoxyethyl-Nxe2x80x2-carboxymethyl ethylenediamine lauryl sulfate, among which 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine is especially preferred. These imidazoline-based amphoteric surfactants are commercially available under trade names such as Amphitol 20YB from Kao Corporation; ENAGICOL C-40H, CNS from Lion Corporation; LEBON 105, CIB from Sanyo Chemical Industries, Ltd.; Obazoline 662Y, 662N, 662SF, CS-65 from Toho Chemical Industry Co., Ltd; Miranol C2M-NP, Miracare 2MCA/P, Miranol ULTRAC-32 from Rhodia Nikka; Rewoteric AM2CNM, AMC from Goldschmidt AG; among which Amphitol 20YB, Obazoline 662N and Miranol ULTRAC-32 can be preferably used.
Imidazoline-based amphoteric surfactants are preferably used in the amount of 0.01-50 parts by weight, more preferably 1-30 parts by weight, even more preferably 3-5 parts by weight per part by weight of propylene glycol hyaluronate esters of the present invention. Compositions containing a propylene glycol hyaluronate ester of the present invention and an imidazoline-based amphoteric surfactant are characterized by less change in viscosity during storage because of their high stability. Especially, propylene glycol hyaluronate esters having an esterification degree of 40-60% provide higher stability as compared with lower esters.
Suitable powders for use in skin preparations for external use according to the present invention include talc, kaolin, fuller earth, gum, starch, silica, silicic acid, aluminium silicate hydrate, chemically modified aluminium magnesium silicate, sodium polyacrylate, tetraalkyl aryl ammonium smectite, trialkyl aryl ammonium smectite, ethylene glycol monostearate, sodium carboxymethylcellulose, carboxyvinyl polymers, chalk, gummy matters, ethylene glycol monostearate, ethylene glycol distearate, etc.
Suitable polyols for use in skin preparations for external use according to the present invention include glycerin, polyglycerins (such as diglycerin, triglycerin, tetraglycerin), ethylene glycol, propylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, dipropylene glycol, polyethylene glycol, sorbitol, erythritol, maltotriose, threitol, sucrose, glucose, maltose, multitose, fructose, xylitose.
Other materials suitable for use in skin preparations for external use according to the present invention include vitamins such as vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K; amino acids such as proline, leucine, isoleucine, alanine, threonine, lysine, cysteine, arginine; hormones such as estrogen, pregnenolone, adrenocortical hormone; peptides such as keratin, collagen, elastin; sugars as listed above for polyols; inorganic salts such as sodium chloride, sodium hydrogencarbonate, sodium carbonate, borax, sodium sulfate, sodium sulfide, sodium thiosulfate, sodium sesquicarbonate, magnesium oxide, calcium carbonate, magnesium carbonate, potassium chloride, potassium sulfide; Streptococcus themophilus cultures; sterols such as cholesterol, provitamin D3, campesterol, stigmastanol, stigmasterol, 5-dihydrocholesterol, xcex1-spinastenol, cholesterol fatty acid esters; sphingosines such as sphingosine, dihydrosphingosine, phytosphingosine, dehydrosphingosine, dehydrophytosphingosine, sphingadienine; ceramides; pseudoceramides; saponins; chitin derivatives; oligosaccharides such as maltose, xylobiose, isomaltose, lactose, sucrose, raffinose, maltotriose, xylotriose, maltotetraose, xylotetraose, maltopentaose, xylopentaose, maltohexaose, xylohexaose, maltoheptaose, xyloheptaose; acid mucopolysaccharides such as hyaluronic acid, chondroitih sulfate, dermatan sulfate, heparin, heparan sulfate; yeast extracts, etc.
Skin preparations for external use according to the present invention may further contain thickeners such as carboxyvinyl polymers, carboxymethylcellulose, polyvinyl alcohol, xanthan gum, carrageenan, alginates, propylene glycol alginate esters, gelatin; electrolytes such as sodium chloride; whitening agents such as arbutin, allantoin, vitamin E derivatives, glycyrrhizin, magnesium ascorbyl phosphate, kojic acid, pantothenic acid derivatives, placenta extract, coix seed extract, green tee, kudzu root, mulberry root, glycyrrhiza, scutellaria root, aloe, orange peel, chamomile, Ganoderma lucidum; skin protective agents such as retinol, retinol esters, retinoic acid; skin softeners such as stearyl alcohol, glyceryl monoricinoleate, mink oil, cetyl alcohol, stearic acid, coconut oil, castor oil, isostearic acid; emollients such as stearyl alcohol, glycerin monoricinoleate, glycerin monostearate, cetyl alcohol; skin penetration enhancers such as 2-methylpropane-2-ol, 2-propanol, ethyl 2-hydroxypropionate, 2,5-hexanediol, acetone, tetrahydrofuran; bioactive plant extracts such as aloe, arnica, glycyrrhiza, sage and swertia herb extracts; preservatives such as p-hydroxybenzoate esters, sodium benzoate, urea, methylparaben, ethylparaben, propylparaben, butylparaben; antiinflammatory agents such as salicylic acid; antibiotics such as triclosan; antioxidants such as xcex1-tocopherol, butylhydroxytoluene; buffers such as triethanolamine or a combination of sodium hydroxide and lactic acid; keratolytic agents such as lactic acid, glycolic acid, malic acid, tartaric acid, citric acid; scrubbing agents such as polyethylene powder; pigments such as calcium, barium or aluminium lake, iron oxide, titanium dioxide, mica, etc.
Skin preparations for external use according to the present invention may also contain other materials depending on the purpose of use. The amount of each ingredient to be added and the method for adding it can be determined by those skilled in the art.